Macrocephaly and Finger Changes: A Narrative Review.

Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.

Inclusion Body Myositis and Neoplasia: A Narrative Review.

Inclusion body myositis (IBM) is an acquired, late-onset inflammatory myopathy, with both inflammatory and degenerative pathogenesis. Although idiopathic inflammatory myopathies may be associated with malignancies, IBM is generally not considered paraneoplastic. Many studies of malignancy in inflammatory myopathies did not include IBM patients. Indeed, IBM is often diagnosed only after around 5 years from onset, while paraneoplastic myositis is generally defined as the co-occurrence of malignancy and myopathy within 1 to 3 years of each other. Nevertheless, a significant association with large granular lymphocyte leukemia has been recently described in IBM, and there are reports of cancer-associated IBM. We review the pathogenic mechanisms supposed to be involved in IBM and outline the common mechanisms in IBM and malignancy, as well as the therapeutic perspectives. The terminally differentiated, CD8+ highly cytotoxic T cells expressing NK features are central in the pathogenesis of IBM and, paradoxically, play a role in some cancers as well. Interferon gamma plays a central role, mostly during the early stages of the disease. The secondary mitochondrial dysfunction, the autophagy and cell cycle dysregulation, and the crosstalk between metabolic and mitogenic pathways could be shared by IBM and cancer. There are intermingled subcellular mechanisms in IBM and neoplasia, and probably their co-existence is underestimated. The link between IBM and cancers deserves further interest, in order to search for efficient therapies in IBM and to improve muscle function, life quality, and survival in both diseases.

Giant ascending aortic aneurysm after aortic valve replacement.

Giant ascending aortic aneurysms are rare clinical entities and are accompanied by a high annual risk of rupture. We present the imaging, intraoperative, and pathology findings of such a case.

A case report of solitary fibrous tumor of the pleura: ultrasound diagnostic features.

Solitary fibrous tumor of the pleura is a rarely encountered clinical entity. Although the majority of these neoplasms have a benign course, the malignant form has also been reported. We describe the case of a 57-year-old male smoker with diabetes who was incidentally diagnosed on chest X-ray with a large solitary mass of the left hemithorax. The diagnostic tests included computed tomography, ultrasound, and contrast-enhanced ultrasound. Radical surgical resection was performed and histological examination confirmed a malignant solitary fibrous tumor of the pleura. The novelty of the case is the use of contrast-enhanced ultrasound in the diagnostic workup.

Platelet-derived growth factor and platelet-derived growth factor receptor-α expression in the normal human thymus and thymoma.

Platelet-derived growth factor (PDGF) and its receptors (PDGFRs) are strongly involved in the normal development of several organs, tumour angiogenesis and malignant progression and metastasis. Few studies concerning their expression, distribution and role in normal and pathological human thymus are available in the literature. The aim of this study has been to analyse the immunohistochemical expression of PDGF and PDGFR-α in prenatal and postnatal normal human thymus and thymomal biopsy specimens. The results demonstrated immunoreactivity to both PDGF and PDGFR-α in all specimens, but the intensity, distribution and number of positive cells were different in normal thymus and thymomas, and also among different tumour types. PDGF and PDGFR-α were weakly expressed in foetal and postnatal humans with a different distribution between cortex and medulla in both blood vessels and epithelial cells, whereas they were overexpressed in thymoma, especially in type B2 and B3, in the tumour epithelial cells. Overall, these data suggest that PDGF and PDGFR-α may be involved in the pathophysiology of the human thymus.

Rare Causes of Arterial Hypertension and Thoracic Aortic Aneurysms-A Case-Based Review.

Thoracic aortic aneurysms may result in dissection with fatal consequences if undetected. A young male patient with no relevant familial history, after having been investigated for hypertension, was diagnosed with an ascending aortic aneurysm involving the aortic root and the proximal tubular segment, associated with a septal atrial defect. The patient underwent a Bentall surgery protocol without complications. Clinical examination revealed dorso-lumbar scoliosis and no other signs of underlying connective tissue disease. Microscopic examination revealed strikingly severe medial degeneration of the aorta, with areas of deep disorganization of the medial musculo-elastic structural units and mucoid material deposition. Genetic testing found a variant of unknown significance the PRKG1 gene encoding the protein kinase cGMP-dependent 1, which is important in blood pressure regulation. There may be genetic links between high blood pressure and thoracic aortic aneurysm determinants. Hypertension was found in FBN1 gene mutations encoding fibrillin and in PRKG1 mutations. Possible mechanisms involving the renin-angiotensin system, the role of oxidative stress, osteopontin, epigenetic modifications and other genes are reviewed. Close follow-up and strict hypertension control are required to reduce the risk of dissection. Hypertension, scoliosis and other extra-aortic signs suggesting a connective tissue disease are possible clues for diagnosis.

Frenemies within: An Endocarditis Case in Behçet's Disease.

A 57-year female patient diagnosed with Behçet's disease, on azathioprine, was noticed to have at a routine examination antinuclear and antiphospholipid antibodies. An overlapping lupus-like syndrome was diagnosed; hydroxychloroquine and aspirin were added. Three years later, the patient presented with dyspnea and sweating, with no fever. A cardiac bruit was noted; a giant vegetation was detected by echocardiography. Laboratory revealed severe thrombocytopenia, antiphospholipid antibodies and low complement. Blood cultures were positive for Abiotrophia defectiva serology and also revealed a chronic Coxiella burnetii infection. Antibiotic therapy, low-dose anticoagulation and control of the underlying disease mildly improved the platelet count, which fully recovered only after cardiac valve replacement. However, the Behçet's disease, initially quiescent, flared after the therapy of infections. We discuss potential links between Behçet's disease and the occurrence of antinuclear and antiphospholipid antibodies and Coxiella endocarditis in this setting. We also highlight the differences between the endocarditis in Behçet's disease, antiphospholipid syndrome, Coxiella burnetii and Abiotrophia defectiva infection, respectively. Intracellular infections may modify the presentation of autoimmune diseases. Confounding clinical features of Coxiella persistent infection and non-bacterial thrombotic endocarditis in Behçet's disease warrant further insight.

Diagnostic and clinical significance of D2-40 expression in the normal human thymus and thymoma.

Human thymus development and thymoma behavior remain elusive, in spite of many acquisitions in the field in last decades. In the present paper, we analyzed the immunohistochemical expression of D2-40 in the normal human thymus and thymoma. In both fetal and postnatal normal thymus, we found a strong expression of D2-40 in the subcapsular and cortico-medullary epithelial cells, and lack of expression in the thymus of involution. These findings support a role for podoplanin in the proliferation of some subtypes of epithelial cells of the normal thymus stroma. In thymoma, the expression of D2-40 was detected in neoplastic cells in 18 from 26 cases (69.23%). No correlation was found between D2-40 expression and histological types of thymoma, but strong correlation was noticed with tumor stage. Based on these results, it is suggested that D2-40 expression is a good predictor of invasion and can be considered as a potential target for therapy in selected cases.

Immunohistochemical expression of vascular endothelial growth factor A (VEGF), and its receptors (VEGFR1, 2) in normal and pathologic conditions of the human thymus.

Vascular endothelial growth factor A (VEGF-A) is an angiogenic growth factor that is a primary stimulant of the vascularization of solid tumors. In the tumor microenvironment, an upregulation of both VEGF and its receptors occurs, leading to a high concentration of occupied receptors on tumor vascular endothelium. Also, VEGF is involved in the development of the normal vascular network of the thymus. Little is known about VEGF expression in normal and malignant thymic tissue. Our purpose was to study the pattern and localization of VEGF expression in benign conditions of the thymus and thymoma to determine a possible correlation with VEGF receptors VEGFR1, VEGFR2 and microvascular density. All cases were positive for VEGF and VEGFR1, 2 in the epithelial cells, in a cytoplasmic, granular pattern. In the normal thymus, there were positive epithelial cells with subcapsular distribution and Hassall's corpuscle epithelial cells. In acute thymic involution, the positive fields were correlated with dilation and stasis of blood vessels and lymphocyte depletion. Rare positive cells were found in other types of involution; the myasthenic thymus showed an intense and diffuse reaction in lymphoid follicles of the medulla. A strong reaction for VEGF was observed in type B3 thymomas in neoplastic epithelial cells, normal endothelial cells, plasma within the blood vessels and focally in the stroma adjacent to the tumor. Receptors for VEGF were positive in neoplastic epithelial cells and endothelium. We hypothesized that VEGF acts as an immunoregulatory factor in the normal thymus and as proangiogenic and autocrine factor in thymomas.

"A ball in a cage".

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Involution of the thymus: a possible diagnostic pitfall.

There were investigated 22 cases from which the thymic tissue was removed either during surgery for cardiovascular malformations (n = 14), or for myasthenia gravis (n = 8). Histological sections were stained with routine morphologic methods, and immunohistochemistry was performed for cytokeratin, CD20, CD3, and S100 protein. Aspects characteristic for thymus involution were found in 11 cases without myasthenia gravis and in all cases with myasthenia gravis. Morphological changes of the thymus of involution are age-dependent. There were characterized stages of involution, with special reference to cortical - medulla inversion, lymphocyte depletion and sequestration. In advanced-stage of involution, epithelial cells are arranged in cords or compact islands, and could mimic a thymoma or a metastatic carcinoma. The immunohistochemical profile is similar but not identical to the active thymus. We noticed a decreased expression of cytokeratin, and a reduced number of CD3, CD20, and S100 positive cells. Morphologic and immunohistochemical peculiarities of the thymus of involution are discussed in relation with the specific pathology of the organ.

Increased mast cell density and microvessel density in the thymus of patients with myasthenia gravis.

There were investigated 15 cases with normal thymus removed during cardiac surgery and nine cases with clinical signs of myasthenia gravis. Four patients with myasthenia gravis had thymoma (three invasive, one non-invasive). Specimens were fixed in buffer formalin, embedded in paraffin and slides were stained with Hematoxylin-Eosin and Alcian blue-Safranin. Additional slides were stained for factor VIII in order to estimate microvessel density. Mast cell density was performed at magnification x400, and microvessel density at magnification x200, using the "hot spot" method. There were found intralobular mast cells in all cases, located mainly in the cortex (6.53 in the normal thymus, 21.4 in patients with myasthenia gravis, and 10 in thymoma-associated myasthenia gravis). A significant increase in the number of intralobular mast cells was noticed in patients with myasthenia gravis without thymoma (p < 0.001), and a moderate increase in patients with thymoma-associated myasthenia gravis (p < 0.023). Values of microvessel density were 10.3 for the normal thymus, 33 for myasthenia gravis without thymoma and 21.8 for myasthenia gravis with associated thymoma. A strong correlation was found between the number of mast cells and microvessel densities in all three conditions.

Effect of the veins histopathological characteristics and preexisting medical conditions on arteriovenous fistula maturation and primary patency in patients with end-stage renal disease: an observational, prospective study.

We assessed the veins histopathological characteristics and preexisting medical conditions before arteriovenous fistula (AVF) creation, and their correlation with AVF outcome and primary patency in patients with end-stage renal disease (ESRD). In this observational, prospective, mono-center study in Romania, patients with artery and venous diameters =2 mm and =2.5 mm, respectively, were enrolled. Vein specimens were harvested at AVF creation and evaluated by Hematoxylin and Eosin, Masson's trichrome and Orcein stainings, in terms of intimal hyperplasia, elastic fibers disposition, medial hypertrophy and smooth muscle cell disorganization and fibrosis (graded from mild to severe). Venous diameters and blood flow one÷two-months post-AVF creation, AVF maturation at dialysis start, two-year primary patency were assessed. Of 115 examined patients, 50 were enrolled and underwent AVF creation. Of six (12%) patients with no vein morphological changes, 11 (22%) with mild histopathological changes, 19 (38%) with moderate and 14 (28%) with severe histopathological changes, four (67%), eight (73%), 17 (89%) and 12 (86%), respectively, had mature AVF. Regardless of histopathological characteristics, non-mature AVF were recorded in older patients and with smaller venous diameter. One÷two-months post-AVF creation, in all patients with mature AVF, venous diameter and ultrasonographic blood flow were similar. Two years post-AVF creation, 26 patients had functional AVF; non-functional AVFs were recorded more likely in women and functional AVFs were most likely located on forearm. The veins histopathological modifications may not negatively influence AVF maturation in ESRD patients. AVF maturation failure may most likely be related to age and venous diameter at AVF creation.

Structural heterogeneity and immunohistochemical profile of Hassall corpuscles in normal human thymus.

The study was conducted on 27 specimens of normal thymus, removed during surgery for cardiovascular malformations. Biopsies were processed using current histological techniques, and the samples were stained using morphological and immunohistochemical methods (cytokeratin profile, vimentin, S100, CD45, CD20, CD3, CD68, CD34 protein, chromogranin A, neuronal-specific enolase, desmin). Microscopic examination focused on the structure and immunohistochemical profile of Hassall corpuscles, beginning from the hypothesis that the epithelial cells of these structures, characteristic for the thymus, participate in the negative and positive selection of thymocytes. Morphological assessment revealed the existence of four different types of Hassall corpuscles: juvenile, immature, mature and senescent. The lymphocyte-rich variant was identified in 25.92% of the cases with ages ranging between 7 days and 12 years. From the immunohistochemical point of view, the following reactions were negative: cytokeratins 7 and 8, vimentin, desmin, CD3, CD68, CD34 and neuron-specific enolase. Isolated positive chromogranin cells were found in two cases, and positive intracorpuscular CD20 cells in one case. Polyclonal cytokeratins were positive in all instances in the epithelial cells of the Hassall corpuscles, with higher intensity in high-molecular weight cytokeratin, strongly expressed in mature corpuscles. All specimens had positive S100 cells in the corpuscles, distributed among the epithelial cells, with dendritic morphology, in great numbers in juvenile and immature forms. Morphological and immunohistochemical results (corpuscle variants, the presence of positive S100 cells, concentration of positive CD20 and CD3 cells around the corpuscles) suggest the active involvement of epithelial cells of Hassall corpuscles in modulating the differentiation of thymocytes at the medullar level, a process that is mediated by protein S100 positive corpuscular dendritic cells.

A very rare association between giant right atrial myxoma and patent foramen ovale. Extracellular matrix and morphological aspects: a case report.

We report a case of sporadic giant cardiac myxoma with a rare localization in the right atrium, operated in our Service, in a 73-year-old female patient who also presented a patent foramen ovale and a history of ischemic stroke in the year prior to current admission. Intra-operatively, the tumor had a very friable, gelatinous aspect, with a high potential for embolization due to its reduced consistency. The present paper refers to clinical, histochemical and immunohistochemical particularities, as well as to macroscopic and microscopic characteristics of the cardiac myxoma, emphasizing the extracellular matrix aspects, and without leaving out the cellular components of this rare tumor, with possible inference in the management of this disease. The authors present their own observations related to the data from the literature. Also, there are some particularities of the case which justify the current presentation.

Lymphocyte-rich Hassall bodies in the normal human thymus.

The study is concerned with the presence of an unusual Lymphocyte-rich type of Hassall body in the normal human thymus. Lymphocyte-rich Hassall bodies are large, they are usually lined by squamous epithelial cells, and contain closely packed lymphocytes in areas with necrotic and hyaline material. Lymphocyte-rich areas of the HassaLL bodies do not contain epithelial cells (as demonstrated with cytokeratin 8/18, 7, 34betaE12, and MNF116), they were negative for CD20 and S100 protein. Immunoreaction for CD3 was positive in 3 of 4 cases. Our results suggest that this type of Hassall body may be involved in the negative selection of thymocytes.

Papillary fibroelastoma of the pulmonary valve: a case report.

Papillary fibroelastoma is a rare, benign cardiac tumor typically found on the heart valves, which is usually discovered incidentally on echocardiography. The clinical presentation of cardiac papillary fibroelastoma varies from no symptoms to severe embolic sequelae. We report the case of a 55-year-old female patient, with a suspicion of pulmonary embolism one year before, presently admitted to the hospital for mild respiratory symptoms; the trans-esophageal echocardiography (TEE) revealed a 10/10 mm tumoral mass attached on the pulmonary valve, confirmed also by the contrast-enhanced magnetic resonance imaging (MRI). Considering the embolization risk, we decided surgical removal, with favorable outcome. The pathologic exam of the removed tumor established the diagnosis of papillary fibroelastoma. The clinical and imaging assessment one month after surgery were within normal limits. The surgical removal of the papillary fibroelastoma of the pulmonary valve is mandatory for the elimination of embolization risk. The intervention is relatively secure, with low rates of morbidity and mortality.

Echocardiography and imaging investigation in congenital cardiovascular anomalies - competition or complementarity? Part II: cyanogenic cardiovascular malformations. Pictorial essay.

The diagnosis of cardiovascular malformations (CVM) is based on the echocardiographic evaluation. Multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) are performant, necessary techniques for the pre- and postoperative assessment of complex malformations, especially of cyanogenic malformations, in which anomalies of the right side of the heart and of the pulmonary circulation are involved and where echocardiography has a limited role. The complementarity of echocardiography with MDCT and MRI for the acquisition of the details necessary for an accurate therapeutic decision and for avoiding invasive exploration, as well as the close relationship between the radiologist and the clinician are crucial and all the more necessary in complex malformations.

Echocardiography and imaging investigation in congenital cardio-vascular anomalies - competition or complementarity? Part I: non-cyanogenic cardiovascular malformations.

Echocardiography is the first technique used for diagnosing cardiovascular malformations (CVM). The results are often completed with multi-detector computer tomography (MDCT) and/or magnetic resonance imaging (MRI) for confirming/ invalidating an abnormal pulmonary venous return in the case of atrial septal defect (ASD) or for the exact interpretation of cardiac function in pre/post-surgery cases with ASD, ventricular septal defect (VSD), and Fallot tetralogy. MDCT and MRI play an important role in the precise and complete diagnosis of Fallot tetralogy, in the anomalies of the right heart cavities and the arterial and venous pulmonary tree, the anomalies of the emergence and course of the coronary arteries, aortic coarctation and developmental anomalies of the aortic arch and supraaortic trunks. The complementarity of echocardiography with MDCT and MRI, in order to obtain details and to avoid invasive procedures and also the cooperation between the pediatrician, cardiologist, surgeon and radiologist, represent the key to the diagnosis and treatment of cardiovascular malformations, for the benefit of the patient.

SOX2 gene expression in normal human thymus and thymoma.

The SOX gene family encodes a large group of transcription factors that are strongly involved in the normal human development and malignancies. Human tumors, like small cell lung carcinoma, meningioma, gastric, and pancreatic cancer, have been found to be immunogenic for SOX2 protein. In this study, we have investigated for the first time the expression and distribution of SOX2 immunoreactive cells in five normal human thymuses (2 fetal and 3 adult) and 10 thymomas bioptic specimens. Results demonstrated the presence of few positive cells in the fetal and postnatal normal human thymus with a specific distribution within thymus parenchyma compartments. On the contrary, in thymoma immunoreactivity to SOX2 increased parallel to pathological stage, and a peculiar distribution was observed in type B3 thymoma with a positive reaction in both tumor and endothelial cells.